Levosimendan for patients with impaired left ventricular function undergoing cardiac surgery
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《血管的通路杂志》
Department of Cardiothoracic Surgery, Prince of Wales Hospital, Barker Street, Randwick, New South Wales, 2031, Australia
Abstract
The efficacy of levosimendan treatment for a low cardiac output status following cardiac surgery has not been established. Here, we review our initial experiences of the perioperative use of levosimendan. This study is a retrospective uncontrolled trial. Nine patients who underwent cardiac surgery, and developed a low cardiac output status resistant to conventional inotropic support, were given levosimendan. The mean preoperative ejection fraction was 35.2±3.4%. All patients were on concomitant inotropic agents and had previously undergone intra-aortic balloon pumping. Cardiac index increased immediately from 2.14±0.33 l/min/m2 at baseline to 2.41±0.31 (P=0.02) at 1 h, rising to 2.67±0.43 (P<0.001) at 4 h after the loading dose was started. Similarly, the systemic vascular resistance index decreased from 2350±525 dynes/s/cm–5/m2 at baseline to 1774±360 (P=0.002) at 4 h. In the case of all but one of the patients, either the dose of the concomitant inotropic support or the balloon pumping could be weaned down within 24 h after completion of the levosimendan infusion. No withdrawal of levosimendan was required. Levosimendan could constitute a new therapeutic option for postoperative low cardiac output.
Key Words: Levosimendan; Postoperative care; Impaired ventricular function
1. Introduction
Despite advanced techniques of myocardial protection, ischemia during aortic cross-clamping and reperfusion of previously hypoperfused areas of myocardium lead to a variable degree of stunning and, frequently, require inotropic support to reverse depressed contractility. This fall in cardiac output, referred to as ‘postoperative low cardiac output syndrome’, contributes to postoperative morbidity and mortality. Most of the currently available inotropic drugs enhance myocardial contractility by increasing concentrations of intracellular calcium, which leads to an increase in myocardial oxygen consumption [1].
Levosimendan is a new calcium-sensitizing agent that has been developed for the treatment of decompensated heart failure. This agent sensitizes troponin C to calcium in a manner that is dependent on calcium concentration, thereby increasing the effects of calcium on cardiac myofilaments during systole, and improving contraction at a low energy [2,3]. Levosimendan also leads to vasodilatation through the opening of ATP-sensitive potassium channels [4]. By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand.
Previous randomized trials have established the favorable hemodynamic effects of intravenously administered levosimendan in patients with severe heart failure [5,6]. Following 6–24 h of levosimendan infusion, hemodynamic parameters improved; improved survival was also seen up to 180 days after the infusion [5]. However, these trial results did not include patients with impaired left ventricular function having undergone cardiac surgery.
Other small-scale studies have demonstrated that levosimendan improved cardiac output and decreased afterload after cardiopulmonary bypass in patients with normal preoperative left ventricular (LV) function [7,8]. These results indicate a potential clinical role for levosimendan in cardiac surgical patients. However, these studies excluded patients with pre-existing LV dysfunction, patients with significant co-morbidities and patients who required other inotropic support. Therefore, the efficacy and safety of levosimendan in the immediate postoperative care period for high-risk patients with impaired cardiac function has not been well established. This study reviews the peri-operative intravenous usage of levosimendan for patients, who developed low cardiac output syndrome that was resistant to conventional inotropic support.
2. Methods
After institutional ethical committee approval, we conducted a retrospective review of the first nine patients to receive intravenous levosimendan as a treatment for severe low cardiac output syndrome following cardiac surgery. In each case, levosimendan was only administered if the patient had a documented preoperative impaired LV systolic function (preoperative ejection fraction 40%), and had developed persistent low cardiac output status (cardiac index 2.2 l/min/m2 with conventional inotropic support). All patients were on concomitant conventional inotropic agents. And also, all patients were either (1) undergoing intra-aortic balloon pumping (IABP) at the time of levosimendan infusion or (2) had undergone IABP although IABP had ceased by the time levosimendan was administered. Levosimendan was given, at the discretion of the intensive care physicians and surgeons, in order to facilitate weaning down of the concomitant inotropic agents and/or IABP.
Levosimendan was administered intravenously in an intensive-care setting through a central venous line; hemodynamics were closely monitored. An initial loading dose of 12 μg/kg levosimendan for 10 min was administered, followed by a continuous infusion of 0.1 μg/kg/min levosimendan for the following 50 min. The infusion rate was increased to 0.2 μg/kg/min levosimendan (high-dose regimen) for a further 23 h if blood pressure was shown to tolerate levosimendan well. If a higher dose was deemed not to be tolerable by the patients, a continuous dose of 0.1 μg/kg/min (low-dose regimen) was used. On completion of the total 24-h dose, the infusion was turned off immediately (no tapering). Typically, concomitant inotropic agents or IABP support was weaned down during or after the administration of levosimendan.
Previously, during and after administration, cardiac output (CO) was measured by a thermo-dilation technique using a pulmonary-artery catheter (n=8) or aortic pulse-contour continuous cardiac output measurement using the PiCCO system (PULSION Medical Systems, Munich, Germany) (n=1). Pulmonary artery and systemic arterial vascular resistance indices were calculated according to standard formulas: PVRI=(MPAP–PCWP)/CI and SVRI=(MAP–CVP)/CI, CI=CO/BSA, where PVRI=pulmonary vascular resistance index, SVRI=systemic vascular resistance index, MAP= mean arterial pressure, CVP=central venous pressure, MPAP=mean PAP, PCWP=pulmonary capillary wedge pressure, CI=cardiac index and BSA=body surface area. As PVRI and MPAP cannnot be obtained by PiCCO system, PVRI and MPAP were analyzed in eight patients while other parameters were calculated in nine patients.
Hemodynamic measurements, as well as other outcomes and complications of the operation, were recorded. Predicted mortality was calculated according to the European system for cardiac operative risk evaluation (additive EuroSCORE) [9].
Statistical analysis was performed using SAS software (Cary, NC) using analysis of variance (ANOVA) with repeated measures. Fisher's protected least significant difference test (PLSD) was used as a post-hoc test to identify significant differences. A P-value of less than 0.05 was considered significant.
3. Results
This review includes five males and four females. The mean age was 67.9±12.6 years. Table 1 shows the demographics of the patients. All patients had experienced New York Heart Association functional class III or IV symptoms of heart failure before the operation. The preoperative ejection fraction was 40% in all patients. Predicted mortality based on the additive EuroSCORE was above 6 in all cases; therefore, all cases were categorized as high-risk cases.
In all patients, IABP was used as perioperative support. Three patients had already been weaned off IABP, and the balloon removed, before the start of levosimendan infusion. Levosimendan was used as post-IABP removal support for these patients. In one patient, levosimendan infusion was started 14 h before the operation. In all other cases, levosimendan infusion was started after the operation. Table 2 shows the clinical situation and concomitant inotropic support at the start of levosimendan infusion.
Table 3 show the changes in hemodynamic parameters at 1 and 4 h after the start of levosimendan infusion. Following the start of the infusion, levosimendan improved cardiac index to a remarkable degree. Cardiac index increased from 2.14±0.33 l/min/m2 at baseline to 2.41±0.31 (P=0.02) at 1 h, rising to 2.67±0.43 (P<0.001) at 4 h. Similarly, heart rate increased from 82.8±6.2 beats per min to 88.3±10.3 (P=0.04) at 1 h and 95.0±9.7 (P=0.005) at 4 h. However, severe tachycardia (with a heart rate of more than 125 beats per min) was not observed in any patients. Systemic vascular resistance index decreased from 2350±525 dynes/s/cm–5/m2 to 1774±360 (P=0.002) at 4 h. There was a slight decrease in pulmonary vascular resistance index; but, it was not statistically significant. Mean arterial pressure was 74.8±8.56 mmHg at baseline and 72.2±16.1 and 72.2±10.1 at 1 h and 4 h, respectively. A drop in mean arterial pressure was observed in some patients; however, this was not statistically significant overall. In fact, in one patient, mean arterial pressure increased when levosimendan was given.
With regard to the concomitant inotropic agents administered during the first 4-h period, the dose of noradrenaline was increased from 0.02 to 0.14 μg/kg/min in one patient, to maintain blood pressure, but was decreased from 0.15 to 0.08 μg/kg/min in another. Thus, the increase observed in cardiac output during this 4-h period would not be due to the change of concomitant inotropic agents.
Table 2 shows the weaning down of concomitant inotropes and IABP at 24 h after the completion of levosimendan infusion (48 h after the start of infusion). In one patient, the dose of concomitant inotropes was unchanged in this period. But, in all other patients, either weaning down of the inotropes or weaning down of IABP was achieved. The patient for whom inotropes could not be weaned down died of multi-organ failure associated with low cardiac output on the thirteenth postoperative day. Of the nine patients, this is the only hospital death that occurred. Other major complications of the operations undertaken are described in Table 2.
No withdrawal of levosimendan was required. During infusion, three patients had hypotensive episodes (mean arterial pressure ranged from 52 to 63 mmHg). These patients required temporary noradrenaline to maintain blood pressure (one patient in the first 4 h and two patients after the first 4 h). There was no new electrocardiographic evidence of myocardial ischemia. Ventricular fibrillation occurred in three patients immediately after the operation; all were successfully resuscitated. Two of them had multiple episodes. As one patient had recurrent ventricular fibrillation, along with poor LV systolic function, he received an implantable defibrillator. No further episode of ventricular fibrillation was observed after the implantation.
4. Discussion
Although some of the data were not statistically significant, the observed hemodynamic effects are consistent with the known pharmacological actions of levosimendan as a calcium sensitizer and a direct vasodilator. Levosimendan appeared to improve the hemodynamic parameters of the post-cardiac surgery patients with impaired LV function. With the use of levosimendan, most patients could be weaned off conventional inotropic support and IABP successfully.
Theoretically, levosimendan has several advantages over conventional inotropic agents. Unlike agents that act through adrenergic pathways, levosimendan does not cause diastolic calcium overload, which can impair myocardial relaxation [10]. Furthermore, it does not increase myocardial oxygen requirements, and may improve myocardial perfusion as a result of vasodilatation [8]. Long-term benefits could also result from levosimendan use, as the presence of a pharmacologically active metabolite with a long elimination half-life (75–80 h) could lead to persistent hemodynamic effects [5].
In our series, three patients had episodes of ventricular fibrillation. However, recent myocardial infarction, poor ejection fraction and high doses of catecholamines can also increase the risk of postoperative ventricular arrhythmia. Thus, it is not clear whether these episodes of ventricular fibrillation were related to levosimendan or not. According to a previous study, which in particular investigated arrhythmia following levosimendan administration, levosimendan has no arrhythmogenic effects, unlike other inotropic agents [11]. Therefore, we think that it is more likely that the episodes of ventricular fibrillation which occurred were related to a recent myocardial infarction and poor LV function. However, further study is needed to clarify this issue.
With regard to other adverse effects, temporary hypotension was an expected but important adverse effect which was well managed through the temporary use of low dose noradrenaline. In some cases, levosimendan led to a degree of peripheral vasodilation which needed to be controlled. Mild tachycardia was also observed, but was not hemodynamically significant. Overall, withdrawal of levosimendan was not required in any of the cases. Therefore, levosimendan can be considered to be a well-tolerated agent which could provide a new treatment option for low cardiac output following cardiac surgery.
This report has significant limitations, as it is a retrospective review of a small number of patients with no controls. The improvement of cardiac output could be due to the effects of the previous operations per se or might be a result of the fact that the myocardium was still recovering from the operation. In addition, cardiac output could be influenced by preload variations. However, the relatively immediate increase of cardiac output and the decrease of vascular resistance observed are both consistent with the previously reported pharmacological studies. Further studies are necessary to clarify the effect and the side effect of levosimendan on postoperative patients.
In summary, this initial assessment indicates that levosimendan could be an effective and well-tolerated agent for the treatment of postoperative low cardiac output in patients with impaired ventricular function. It could be effectively used to facilitate the weaning down of conventional inotropic agents or IABP.
References
Packer M. The search for the ideal positive inotropic agent. N Engl J Med 1993; 329:201–202.
Ukkonen H, Saraste M, Akkila J, Knuuti J, Karanko M, Iida H, Lehikoinen P, Nagren K, Lehtonen L, Voipio-Pulkki LM. Myocardial efficiency during levosimendan infusion in congestive heart failure. J Clin Pharmacol Ther 2000; 68:522–531.
Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H. Influence of the novel inotropic agent levosimendan on isometrictension and calcium cycling in failing human myocardium. Circulation 1998; 98:2141–2147.
Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. Levosimendan, a novel Ca2+ – sensitizer activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Eur J Pharmacol 1997; 333:249–259.
Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, Harjola VP, Mitrovic V, Abdalla M, Sandell EP, Lehtonen L. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 2002; 360:196–202.
Slawsky MT, Colucci WS, Gottlieb SS, Greenberg BH, Haeusslein E, Hare J, Hutchins S, Leier CV, LeJemtel TH, Loh E, Nicklas J, Ogilby D, Singh BN, Smith W. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation 2000; 102:2222–2227.
Nijhawan N, Nicolosi AC, Montgomery MW, Aggarwal A, Pagel PS, Warltier DC. Levosimendan enhances cardiac performance after cardiopulmonary bypass: a prospective, randomized placebo-controlled trial. J Cardiovasc Pharmacol 1999; 34:219–228.
Lilleberg J, Nieminen MS, Akkila J, Heikkila L, Kuitunen A, Lehtonen L, Verkkala K, Mattila S, Salmenpera M. Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J 1998; 19:660–668.
Nashef SAM, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. the EuroSCORE study group. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999; 16:9–13.
Haikala H, Nissinen E, Etemadzadeh E, levijoki J, Linden I-B. Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation. J Cardiovasc Pharmacol 1995; 25:794–801.
Singh BN, Lilleberg J, Sandell EP, Ylnen V, Lehtonen L, Toivonen L. Effects of levosimendan on cardiac arrhythmia: electrophysiologic and ambulatory electrocardiographic findings in phase II and phase III clinical studies in cardiac failure. Am J Cardiol 1999; 83:16–20.(Yoshiyuki Tokuda, Peter W)
Abstract
The efficacy of levosimendan treatment for a low cardiac output status following cardiac surgery has not been established. Here, we review our initial experiences of the perioperative use of levosimendan. This study is a retrospective uncontrolled trial. Nine patients who underwent cardiac surgery, and developed a low cardiac output status resistant to conventional inotropic support, were given levosimendan. The mean preoperative ejection fraction was 35.2±3.4%. All patients were on concomitant inotropic agents and had previously undergone intra-aortic balloon pumping. Cardiac index increased immediately from 2.14±0.33 l/min/m2 at baseline to 2.41±0.31 (P=0.02) at 1 h, rising to 2.67±0.43 (P<0.001) at 4 h after the loading dose was started. Similarly, the systemic vascular resistance index decreased from 2350±525 dynes/s/cm–5/m2 at baseline to 1774±360 (P=0.002) at 4 h. In the case of all but one of the patients, either the dose of the concomitant inotropic support or the balloon pumping could be weaned down within 24 h after completion of the levosimendan infusion. No withdrawal of levosimendan was required. Levosimendan could constitute a new therapeutic option for postoperative low cardiac output.
Key Words: Levosimendan; Postoperative care; Impaired ventricular function
1. Introduction
Despite advanced techniques of myocardial protection, ischemia during aortic cross-clamping and reperfusion of previously hypoperfused areas of myocardium lead to a variable degree of stunning and, frequently, require inotropic support to reverse depressed contractility. This fall in cardiac output, referred to as ‘postoperative low cardiac output syndrome’, contributes to postoperative morbidity and mortality. Most of the currently available inotropic drugs enhance myocardial contractility by increasing concentrations of intracellular calcium, which leads to an increase in myocardial oxygen consumption [1].
Levosimendan is a new calcium-sensitizing agent that has been developed for the treatment of decompensated heart failure. This agent sensitizes troponin C to calcium in a manner that is dependent on calcium concentration, thereby increasing the effects of calcium on cardiac myofilaments during systole, and improving contraction at a low energy [2,3]. Levosimendan also leads to vasodilatation through the opening of ATP-sensitive potassium channels [4]. By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand.
Previous randomized trials have established the favorable hemodynamic effects of intravenously administered levosimendan in patients with severe heart failure [5,6]. Following 6–24 h of levosimendan infusion, hemodynamic parameters improved; improved survival was also seen up to 180 days after the infusion [5]. However, these trial results did not include patients with impaired left ventricular function having undergone cardiac surgery.
Other small-scale studies have demonstrated that levosimendan improved cardiac output and decreased afterload after cardiopulmonary bypass in patients with normal preoperative left ventricular (LV) function [7,8]. These results indicate a potential clinical role for levosimendan in cardiac surgical patients. However, these studies excluded patients with pre-existing LV dysfunction, patients with significant co-morbidities and patients who required other inotropic support. Therefore, the efficacy and safety of levosimendan in the immediate postoperative care period for high-risk patients with impaired cardiac function has not been well established. This study reviews the peri-operative intravenous usage of levosimendan for patients, who developed low cardiac output syndrome that was resistant to conventional inotropic support.
2. Methods
After institutional ethical committee approval, we conducted a retrospective review of the first nine patients to receive intravenous levosimendan as a treatment for severe low cardiac output syndrome following cardiac surgery. In each case, levosimendan was only administered if the patient had a documented preoperative impaired LV systolic function (preoperative ejection fraction 40%), and had developed persistent low cardiac output status (cardiac index 2.2 l/min/m2 with conventional inotropic support). All patients were on concomitant conventional inotropic agents. And also, all patients were either (1) undergoing intra-aortic balloon pumping (IABP) at the time of levosimendan infusion or (2) had undergone IABP although IABP had ceased by the time levosimendan was administered. Levosimendan was given, at the discretion of the intensive care physicians and surgeons, in order to facilitate weaning down of the concomitant inotropic agents and/or IABP.
Levosimendan was administered intravenously in an intensive-care setting through a central venous line; hemodynamics were closely monitored. An initial loading dose of 12 μg/kg levosimendan for 10 min was administered, followed by a continuous infusion of 0.1 μg/kg/min levosimendan for the following 50 min. The infusion rate was increased to 0.2 μg/kg/min levosimendan (high-dose regimen) for a further 23 h if blood pressure was shown to tolerate levosimendan well. If a higher dose was deemed not to be tolerable by the patients, a continuous dose of 0.1 μg/kg/min (low-dose regimen) was used. On completion of the total 24-h dose, the infusion was turned off immediately (no tapering). Typically, concomitant inotropic agents or IABP support was weaned down during or after the administration of levosimendan.
Previously, during and after administration, cardiac output (CO) was measured by a thermo-dilation technique using a pulmonary-artery catheter (n=8) or aortic pulse-contour continuous cardiac output measurement using the PiCCO system (PULSION Medical Systems, Munich, Germany) (n=1). Pulmonary artery and systemic arterial vascular resistance indices were calculated according to standard formulas: PVRI=(MPAP–PCWP)/CI and SVRI=(MAP–CVP)/CI, CI=CO/BSA, where PVRI=pulmonary vascular resistance index, SVRI=systemic vascular resistance index, MAP= mean arterial pressure, CVP=central venous pressure, MPAP=mean PAP, PCWP=pulmonary capillary wedge pressure, CI=cardiac index and BSA=body surface area. As PVRI and MPAP cannnot be obtained by PiCCO system, PVRI and MPAP were analyzed in eight patients while other parameters were calculated in nine patients.
Hemodynamic measurements, as well as other outcomes and complications of the operation, were recorded. Predicted mortality was calculated according to the European system for cardiac operative risk evaluation (additive EuroSCORE) [9].
Statistical analysis was performed using SAS software (Cary, NC) using analysis of variance (ANOVA) with repeated measures. Fisher's protected least significant difference test (PLSD) was used as a post-hoc test to identify significant differences. A P-value of less than 0.05 was considered significant.
3. Results
This review includes five males and four females. The mean age was 67.9±12.6 years. Table 1 shows the demographics of the patients. All patients had experienced New York Heart Association functional class III or IV symptoms of heart failure before the operation. The preoperative ejection fraction was 40% in all patients. Predicted mortality based on the additive EuroSCORE was above 6 in all cases; therefore, all cases were categorized as high-risk cases.
In all patients, IABP was used as perioperative support. Three patients had already been weaned off IABP, and the balloon removed, before the start of levosimendan infusion. Levosimendan was used as post-IABP removal support for these patients. In one patient, levosimendan infusion was started 14 h before the operation. In all other cases, levosimendan infusion was started after the operation. Table 2 shows the clinical situation and concomitant inotropic support at the start of levosimendan infusion.
Table 3 show the changes in hemodynamic parameters at 1 and 4 h after the start of levosimendan infusion. Following the start of the infusion, levosimendan improved cardiac index to a remarkable degree. Cardiac index increased from 2.14±0.33 l/min/m2 at baseline to 2.41±0.31 (P=0.02) at 1 h, rising to 2.67±0.43 (P<0.001) at 4 h. Similarly, heart rate increased from 82.8±6.2 beats per min to 88.3±10.3 (P=0.04) at 1 h and 95.0±9.7 (P=0.005) at 4 h. However, severe tachycardia (with a heart rate of more than 125 beats per min) was not observed in any patients. Systemic vascular resistance index decreased from 2350±525 dynes/s/cm–5/m2 to 1774±360 (P=0.002) at 4 h. There was a slight decrease in pulmonary vascular resistance index; but, it was not statistically significant. Mean arterial pressure was 74.8±8.56 mmHg at baseline and 72.2±16.1 and 72.2±10.1 at 1 h and 4 h, respectively. A drop in mean arterial pressure was observed in some patients; however, this was not statistically significant overall. In fact, in one patient, mean arterial pressure increased when levosimendan was given.
With regard to the concomitant inotropic agents administered during the first 4-h period, the dose of noradrenaline was increased from 0.02 to 0.14 μg/kg/min in one patient, to maintain blood pressure, but was decreased from 0.15 to 0.08 μg/kg/min in another. Thus, the increase observed in cardiac output during this 4-h period would not be due to the change of concomitant inotropic agents.
Table 2 shows the weaning down of concomitant inotropes and IABP at 24 h after the completion of levosimendan infusion (48 h after the start of infusion). In one patient, the dose of concomitant inotropes was unchanged in this period. But, in all other patients, either weaning down of the inotropes or weaning down of IABP was achieved. The patient for whom inotropes could not be weaned down died of multi-organ failure associated with low cardiac output on the thirteenth postoperative day. Of the nine patients, this is the only hospital death that occurred. Other major complications of the operations undertaken are described in Table 2.
No withdrawal of levosimendan was required. During infusion, three patients had hypotensive episodes (mean arterial pressure ranged from 52 to 63 mmHg). These patients required temporary noradrenaline to maintain blood pressure (one patient in the first 4 h and two patients after the first 4 h). There was no new electrocardiographic evidence of myocardial ischemia. Ventricular fibrillation occurred in three patients immediately after the operation; all were successfully resuscitated. Two of them had multiple episodes. As one patient had recurrent ventricular fibrillation, along with poor LV systolic function, he received an implantable defibrillator. No further episode of ventricular fibrillation was observed after the implantation.
4. Discussion
Although some of the data were not statistically significant, the observed hemodynamic effects are consistent with the known pharmacological actions of levosimendan as a calcium sensitizer and a direct vasodilator. Levosimendan appeared to improve the hemodynamic parameters of the post-cardiac surgery patients with impaired LV function. With the use of levosimendan, most patients could be weaned off conventional inotropic support and IABP successfully.
Theoretically, levosimendan has several advantages over conventional inotropic agents. Unlike agents that act through adrenergic pathways, levosimendan does not cause diastolic calcium overload, which can impair myocardial relaxation [10]. Furthermore, it does not increase myocardial oxygen requirements, and may improve myocardial perfusion as a result of vasodilatation [8]. Long-term benefits could also result from levosimendan use, as the presence of a pharmacologically active metabolite with a long elimination half-life (75–80 h) could lead to persistent hemodynamic effects [5].
In our series, three patients had episodes of ventricular fibrillation. However, recent myocardial infarction, poor ejection fraction and high doses of catecholamines can also increase the risk of postoperative ventricular arrhythmia. Thus, it is not clear whether these episodes of ventricular fibrillation were related to levosimendan or not. According to a previous study, which in particular investigated arrhythmia following levosimendan administration, levosimendan has no arrhythmogenic effects, unlike other inotropic agents [11]. Therefore, we think that it is more likely that the episodes of ventricular fibrillation which occurred were related to a recent myocardial infarction and poor LV function. However, further study is needed to clarify this issue.
With regard to other adverse effects, temporary hypotension was an expected but important adverse effect which was well managed through the temporary use of low dose noradrenaline. In some cases, levosimendan led to a degree of peripheral vasodilation which needed to be controlled. Mild tachycardia was also observed, but was not hemodynamically significant. Overall, withdrawal of levosimendan was not required in any of the cases. Therefore, levosimendan can be considered to be a well-tolerated agent which could provide a new treatment option for low cardiac output following cardiac surgery.
This report has significant limitations, as it is a retrospective review of a small number of patients with no controls. The improvement of cardiac output could be due to the effects of the previous operations per se or might be a result of the fact that the myocardium was still recovering from the operation. In addition, cardiac output could be influenced by preload variations. However, the relatively immediate increase of cardiac output and the decrease of vascular resistance observed are both consistent with the previously reported pharmacological studies. Further studies are necessary to clarify the effect and the side effect of levosimendan on postoperative patients.
In summary, this initial assessment indicates that levosimendan could be an effective and well-tolerated agent for the treatment of postoperative low cardiac output in patients with impaired ventricular function. It could be effectively used to facilitate the weaning down of conventional inotropic agents or IABP.
References
Packer M. The search for the ideal positive inotropic agent. N Engl J Med 1993; 329:201–202.
Ukkonen H, Saraste M, Akkila J, Knuuti J, Karanko M, Iida H, Lehikoinen P, Nagren K, Lehtonen L, Voipio-Pulkki LM. Myocardial efficiency during levosimendan infusion in congestive heart failure. J Clin Pharmacol Ther 2000; 68:522–531.
Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H. Influence of the novel inotropic agent levosimendan on isometrictension and calcium cycling in failing human myocardium. Circulation 1998; 98:2141–2147.
Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. Levosimendan, a novel Ca2+ – sensitizer activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Eur J Pharmacol 1997; 333:249–259.
Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, Harjola VP, Mitrovic V, Abdalla M, Sandell EP, Lehtonen L. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 2002; 360:196–202.
Slawsky MT, Colucci WS, Gottlieb SS, Greenberg BH, Haeusslein E, Hare J, Hutchins S, Leier CV, LeJemtel TH, Loh E, Nicklas J, Ogilby D, Singh BN, Smith W. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation 2000; 102:2222–2227.
Nijhawan N, Nicolosi AC, Montgomery MW, Aggarwal A, Pagel PS, Warltier DC. Levosimendan enhances cardiac performance after cardiopulmonary bypass: a prospective, randomized placebo-controlled trial. J Cardiovasc Pharmacol 1999; 34:219–228.
Lilleberg J, Nieminen MS, Akkila J, Heikkila L, Kuitunen A, Lehtonen L, Verkkala K, Mattila S, Salmenpera M. Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J 1998; 19:660–668.
Nashef SAM, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. the EuroSCORE study group. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999; 16:9–13.
Haikala H, Nissinen E, Etemadzadeh E, levijoki J, Linden I-B. Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation. J Cardiovasc Pharmacol 1995; 25:794–801.
Singh BN, Lilleberg J, Sandell EP, Ylnen V, Lehtonen L, Toivonen L. Effects of levosimendan on cardiac arrhythmia: electrophysiologic and ambulatory electrocardiographic findings in phase II and phase III clinical studies in cardiac failure. Am J Cardiol 1999; 83:16–20.(Yoshiyuki Tokuda, Peter W)